Exposure to perfluoroalkyl substances (PFAS) may be harmful to humans; however, previous studies have been inconsistent regarding the potential for PFAS-induced immunosuppresion. This study explored the relationship between PFAS exposure and risks of asthma, wheezing, and immunosuppression in 12-19 year-olds using the National Health and Nutrition Examination Survey (NHANES) data. Logistic regression models were used to reveal associations between serum PFAS levels and risks of asthma, wheezing, asthma attack, and emergency department visits. Pearson’s correlation was used to determine the relationship between serum PFAS levels and leukocyte count. Data were also stratified by sex. We found that medium-low levels of serum perfluorooctane sulfonate (PFOS) (6.90-12.40 ng/mL) and serum perfluorooctanoic acid (PFOA) (2.43-3.60 ng/mL) were negatively related, respectively, to current asthma and wheezing in boys, and to wheezing in girls. Meanwhile, boys with medium-high levels (1.50-3.00 ng/mL) of serum perfluorohexanesulfonate (PFHxS) had a high risk of wheezing. Among asthmatic participants, both medium-high levels (3.75-5.07 ng/mL) of serum PFOA and high levels (> 3.92 ng/mL) of PFHxS correlated with asthma attacks in boys; likewise, medium-low levels (0.70-0.99 ng/mL) of serum PFNA correlated with asthma attacks in girls. Also, PFOA and PFNA levels were weakly positively correlated with basophil count, whereas PFOS levels were weakly negatively correlated with eosinophils in asthmatic boys, indicating that basophils may be important in the immune response to PFAS exposure among asthmatics.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.